Alcohol dependence and tobacco smoking are highly associated, yet studies examining the underlying neurochemistry are scarce. In humans, tobacco smoking appears to regulate the availability of the GABAA- BZR during the recovery from alcohol dependence. Clinical data suggest increased GABAA-BZR availability in alcohol dependent nonsmokers during acute withdrawal that is suppressed in alcohol dependent smokers. Additionally, there appears to be decreased GABAA-BZR availability during prolonged alcohol withdrawal;yet this has not been systematically studied. The purpose of this project is to determine the effects of withdrawal from chronic orally-delivered ethanol versus chronic co-administration of ethanol and nicotine on the GABAA- BZR in brain over time using [123I]iomazenil and single photon emission computed tomography (SPECT). We will also examine changes in GABAA-BZR availability during withdrawal from both ethanol and nicotine simultaneously, versus withdrawal from ethanol in the presence of continued nicotine exposure to model changes in GABAA-BZR in humans that quit drinking and smoking simultaneously vs. quitting drinking while continuing to smoke. We will obtain scans in 50 adolescent animals (n=10 per group). All animals will receive 2 scans at baseline, e.g., test-retest. Group 1 will self-administer chronic ethanol for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 2 will self-administer chronic nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 3A will self-administer ethanol plus nicotine for 24 weeks and will be scanned at 1 day, 8 days and 12 weeks withdrawal from both ethanol and nicotine. Group 3B will self-administer ethanol plus nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal from ethanol, but will continue to self-administer nicotine during this withdrawal period. Group 4, a control condition, will self-administer saccharin for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks after termination of saccharin. MRI scans will be obtained to track changes in brain gray and white matter and cerebrospinal fluid (CSF). We hypothesize that there will be 1) increased GABAA-BZR availability compared to baseline and controls during acute ethanol withdrawal and decreased GABAA-BZR availability compared to baseline and controls at 12 weeks ethanol withdrawal;2) no change in GABAA-BZR availability compared to baseline or controls during nicotine withdrawal;and, 3) the combination of ethanol and nicotine will result in decreased GABAA-BZR availability compared to ethanol alone, i.e., nicotine will suppress the ethanol-induced increase, and withdrawal from ethanol into the presence of nicotine will result in a greater suppression of increased GABAA-BZR availability compared to withdrawal from ethanol and nicotine simultaneously. The findings from this study will advance the understanding of the neurochemical mechanisms that underlie the high comorbidity of alcohol and nicotine dependence and will have direct clinical implications for the treatment of alcohol dependence in both smokers and nonsmokers. PUBLIC HEALTH RELEVANCE: The proposed experiments will directly impact public health by delineating a brain mechanism, the GABAA- benzodiazepine receptor, which is involved in the recovery from alcohol dependence and in the interaction of alcohol dependence and tobacco smoking. These studies will examine the withdrawal from both alcohol and nicotine to determine the interaction of these drugs on brain chemistry. These studies will ultimately provide information on how to more successfully treat these costly addictions.